Effect of Denosumab Added to 2 Different nab-Paclitaxel Regimens as Neoadjuvant Therapy in Patients With Primary Breast Cancer
Authors: Jens-Uwe Blohmer, Theresa Link, Mattea Reinisch, Marianne Just, Michael Untch, Oliver Stötzer, Peter A. Fasching, Andreas Schneeweiss, Pauline Wimberger, Sabine Seiler, Jens Huober, Marc Thill, Christian Jackisch, Kerstin Rhiem, Christine Solbach, Claus Hanusch, Fenja Seither, Carsten Denkert, Knut Engels, Valentina Nekljudova, Sibylle Loibl, Bernhard Heinrich, Jens-Uwe Blohmer, Jörg Schilling, Marianne Just, Stefan Renner, Ute Bückner, Petra Krabisch, Walther Kuhn, Georg Kunz, Pauline Wimberger, Tanja Fehm, Sherko Kümmel, Oliver Hofmann, Joachim Rom, Marc Thill, Hans Tesch, Thomas Noesselt, Frank Holms, Kristina Lübbe, Julia Radosa, Oliver Tomé, Sabine Schmatloch, Jörg Thomalla, Mathias Warm, Oliver Stötzer, Matthias Frank, Michaela Penlope Wüllner, Alex Paulenz, Thomas Decker, Michael Weigel, Manfred Hofman, Eike Simon, Christoph Jung, Rolf Mahlberg, Andreas Hartkopf, Cristin Kühn, Stefanie Buchen, John Hackmann
Journal: JAMA Oncology (2022)

<h3>Importance</h3> Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)–positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear. <h3>Objective</h3> To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting. <h3>Design, Setting, and Participants</h3> The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or<i>ERBB2</i>(formerly<i>HER2</i>)–positive BC. <h3>Interventions</h3> Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m<sup>2</sup>weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m<sup>2</sup>(every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in<i>ERBB2</i>-positive BC (<i>ERBB2</i>-positive substudy). <h3>Main Outcomes and Measures</h3> The primary outcome was pCR rates between arms for each randomization. <h3>Results</h3> A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (<i>P</i> = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (<i>P</i> = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%;<i>P</i> = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%;<i>P</i> = .004). <h3>Conclusions and Relevance</h3> In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m<sup>2</sup>weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT02682693